The therapeutic mechanism of antidepressant drugs possibly includes their effects on the circadian system. This possibility is being examined by testing the effects of antidepressant and neuroleptic drugs on the state of the circadian pacemaker that controls daily rhythms of motor activity, temperature and EEG sleep. Our recent investigations have focused on the effects of chronic psychoactive drug treatment on the circadian pattern of temperature within the hypothalamus, the brain region containing the circadian pacemaker as well as central thermostat which regulates body temperature. These experiments have shown that antidepressant drugs and neuroleptic drugs increase and decrease respectively, the circadian amplitude of hypothalamic temperature. More specifically, chronic antidepressant drug treatments decrease hypothalamic temperature during the rest (light) phase. The neuroleptic drugs (chlorpromazine and haloperidol) increase hypothalamic temperature during the rest phase. Hypothalamic cooling is likely to involve serotonergic properties of the drugs. Antidepressant drugs may alter hypothalamic temperature by changing cerebral arterial blood flow or venous drainage at the base of the hypothalamus. The fact that each of the antidepressant drugs decreased Th, but some failed to phase-delay the daily rhythm in Th, suggests that the former may be more closely associated with the antidepressant mechanism than the latter. In depressed patients, elevated body temperature is often observed during nocturnal rest, and pharmacological and non-pharmacological treatments of depression have been reported to lower body temperature. Therefore, the findings that antidepressant drugs decrease hypothalamic temperature may be important in understanding their therapeutic mechanism. Drug-treated hamsters prefer warmer ambient temperatures than controls, indicating the hamsters are utilizing behavioral thermoregulation to compensate for the drug-induced decrease in Th. Antidepressant drugs decrease hypothalamic temperature (Th), but not the set-point as measured by resting oxygen consumption. These two observations, as well as the observations that cortisol and motor activity levels increase in drug treated hamsters, suggests that drug treatment may activate cold defense mechanisms. A second area of investigation has been to determine the role of serotonin in modulating the circadian system response to light, as well as the reverse relationship: the role of light in modulating circadian variation of serotonin. Analysis of light effects on 5HT levels measured in discrete brain nuclei indicates that 5HT levels increase in terminal regions but not in cell bodies during acute light exposure. The data suggest that light differentially affects 5HT metabolism within different brain regions.